Department of Molecular Genetics, University of Toronto, Toronto, Canada.
PLoS Genet. 2010 Nov 4;6(11):e1001187. doi: 10.1371/journal.pgen.1001187.
The frequent dispensability of duplicated genes in budding yeast is heralded as a hallmark of genetic robustness contributed by genetic redundancy. However, theoretical predictions suggest such backup by redundancy is evolutionarily unstable, and the extent of genetic robustness contributed from redundancy remains controversial. It is anticipated that, to achieve mutual buffering, the duplicated paralogs must at least share some functional overlap. However, counter-intuitively, several recent studies reported little functional redundancy between these buffering duplicates. The large yeast genetic interactions released recently allowed us to address these issues on a genome-wide scale. We herein characterized the synthetic genetic interactions for ∼500 pairs of yeast duplicated genes originated from either whole-genome duplication (WGD) or small-scale duplication (SSD) events. We established that functional redundancy between duplicates is a pre-requisite and thus is highly predictive of their backup capacity. This observation was particularly pronounced with the use of a newly introduced metric in scoring functional overlap between paralogs on the basis of gene ontology annotations. Even though mutual buffering was observed to be prevalent among duplicated genes, we showed that the observed backup capacity is largely an evolutionarily transient state. The loss of backup capacity generally follows a neutral mode, with the buffering strength decreasing in proportion to divergence time, and the vast majority of the paralogs have already lost their backup capacity. These observations validated previous theoretic predictions about instability of genetic redundancy. However, departing from the general neutral mode, intriguingly, our analysis revealed the presence of natural selection in stabilizing functional overlap between SSD pairs. These selected pairs, both WGD and SSD, tend to have decelerated functional evolution, have higher propensities of co-clustering into the same protein complexes, and share common interacting partners. Our study revealed the general principles for the long-term retention of genetic redundancy.
在芽殖酵母中，重复基因的频繁非必需性被认为是遗传冗余带来的遗传稳健性的标志。然而，理论预测表明，这种冗余备份在进化上是不稳定的，冗余所带来的遗传稳健性的程度仍然存在争议。人们预计，为了实现相互缓冲，重复的同源基因至少必须共享一些功能重叠。然而，与直觉相反，最近的几项研究报告称，这些缓冲重复之间的功能冗余很少。最近发布的大型酵母遗传相互作用数据使我们能够在全基因组范围内解决这些问题。我们在这里对来自全基因组复制（WGD）或小规模复制（SSD）事件的约 500 对酵母重复基因的合成遗传相互作用进行了表征。我们确定了重复基因之间的功能冗余是备份能力的先决条件，因此具有高度的预测性。这一观察结果在使用新引入的基于基因本体注释的同源基因之间功能重叠评分指标时尤为明显。尽管观察到重复基因之间存在相互缓冲，但我们表明观察到的备份能力在很大程度上是一种进化上的瞬态状态。备份能力的丧失通常遵循一种中性模式，缓冲强度与分化时间成比例下降，并且绝大多数同源基因已经失去了备份能力。这些观察结果验证了先前关于遗传冗余不稳定性的理论预测。然而，与一般的中性模式不同，有趣的是，我们的分析揭示了自然选择在稳定 SSD 对之间的功能重叠方面的存在。这些被选择的同源基因，无论是 WGD 还是 SSD，往往具有减缓的功能进化，具有更高的倾向共同聚类到相同的蛋白质复合物中，并且共享共同的相互作用伙伴。我们的研究揭示了长期保留遗传冗余的一般原则。
